Leptin is an adipose tissue derived hormone with potent weight-reducing and other effects. Mice and humans with mutation of the gene encoding leptin or its receptor develop morbid obesity. Our long-term objectives are to understand the molecular regulation of mammalian body weight and the mechanisms by which obesity contributes to the development of diabetes. Our general strategy is to focus on the characterization of the signal transduction pathway used by the leptin receptors. Our specific aims during the proposed grant period are: (1) To determine the function of STAT3 in pancreatic beta cells. We used Cre/Lox technology to delete STAT3 from the pancreatic beta cells only to determine how beta cell function and islet development are altered in the absence of STAT3. (2) To determine the function of STAT3 in leptin receptor signaling in pancreatic beta cells. We will compare leptin signaling properties in cells from mice generated in (1) and mice with Y 11 38-F mutation of the leptin receptor that has lost the ability to activate STAT3. (3) To determine the primary functional defect of the leptin receptor in Zucker diabetic fatty rats caused by a single amino acid substitution (Gln269->Pro). We will examine each step of leptin signaling to determine the primary functional defect of the leptin receptor in these rats. A better understanding of the signal transduction pathway used by leptin may reveal novel strategies to enhance or inhibit leptin's biological activities for therapeutic purposes.